Presentation: Child acutely unwell in NICU or PICU

A neonate is delivered at 32 weeks’ gestation due to fetal distress. Antenatal imaging revealed fetal hydrops with ascites, bilateral pleural effusions and a pericardial effusion, the cause of which is unknown. Since birth, the neonate has remained critically unwell in NICU and has dysmorphic features including low-set ears, micrognathia, widely spaced nipples and a flat nasal bridge.

Consider genomic testing if:

• a neonate or child is admitted to NICU or PICU with a likely single gene cause for their presentation (monogenic disorder);
• a neonate or child is admitted to NICU or PICU with any of the following (and an alternate diagnosis is unavailable):
  • congenital anomalies (two major or one major together with neurological signs, dysmorphic features, aberrant growth or unusual behaviour);
  • neurological signs (such as seizures, encephalopathy and hyper- or hypotonia);
  • suspected metabolic or mitochondrial disease; and/or
  • extreme intrauterine growth restriction or failure to thrive; and/or
• a critically unwell neonate or child presents without a clear unifying diagnosis.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family and discuss the case with your local clinical geneticist. For acutely unwell children in NICU or PICU, the following panels should be considered:
  • R14: This should be considered if the patient fulfils the criteria for rapid whole genome sequencing (WGS). The criteria are: the patient is acutely unwell, there is a likely monogenic disorder, and molecular diagnosis is likely to imminently alter management;
  • R26 Likely common aneuploidy testing: This should be performed first if aneuploidy (trisomy 13, trisomy 18 or trisomy 21) is considered to be the most likely diagnosis (for more information, see Common aneuploidy testing (QF-PCR));
  • R28 Congenital malformation and dysmorphism syndromes (microarray): This should be considered if a multisystem syndrome with a possible chromosomal diagnosis is suspected; and
  • R27 Congenital malformation and dysmorphism syndromes: This includes microarray and a WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and may be considered for patients who require broad genomic testing but who are not eligible for R14. Additional panels relevant to the patient phenotype can also be added where trio analysis (analysis of both parents and child) is requested.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents. Include details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS, including R26 and R28:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• The majority of tests are DNA-based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• R27 is a large WGS super panel, and requesting it currently requires authorisation from clinical genetics.
• R14 is a WGS test that looks agnostically across the entire genome. Requesting it currently requires authorisation from clinical genetics. There is a special test order form and RoD form for this test, both of which are available from the Exeter Genetics Laboratory.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Exeter Genetic Laboratory: Exome sequencing service
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• French CE, Delon I, Dolling H and others. ‘Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children’. Intensive Care Medicine 2019: volume 45, issue 5, pages 627–636. DOI: 0.1007/s00134-019-05552-x
• Sparks TN, Lianoglou BR, Adami RR and others. ‘Exome sequencing for prenatal diagnosis in nonimmune hydrops fetalis’. The New England Journal of Medicine 2020: volume 383, issue 18, pages 1,746–1,756. DOI: 10.1056/NEJMoa2023643

For patients

• NHS England: Whole genome sequencing patient information leaflets